This invention relates to a formulation and method for preparing a granulated acetaminophen composition suitable for direct compression into tablets.
A tablet is a complex dosage form of blends of particulate solid materials comprising active pharmaceutical ingredients. Ease of administration and availability in a variety of shapes and sizes make tablets a universally accepted and most commonly used oral dosage form. Tablets are compressed from blends of particulate solid materials with good flow and compressibility characteristics, which, in many instances, have been pregranulated to promote compressibility into a tablet. In addition to an active drug, a tablet blend may contain several inactive but essential ingredients, such as binder, bulking agent, disintegrant, flow enhancer, lubricant, etc. In general, the principal methods used by the pharmaceutical industry to prepare tablet blends are:
Direct Compression or Dry Blend--A dry blend suitable for direct compression is prepared by a simple mixing process. This is the preferred method for low dose drugs and for drugs that inherently possess good compression characteristics. Simplicity of the method and resulting advantages of time and resource savings make this a very desirable method for tablet manufacturers. PA1 Dry Granulation--A dry granulation is prepared by compacting a dry powder blend of the drug and inactive tableting ingredients using roller compacting or slugging equipment, milling the compact and blending the resultant granulation with other inactive ingredients. This method is commonly used for blends of drugs that are compressible but do not have required flow characteristics or for drugs that have marginal compressibility, e.g., aspirin. Dry granulation requires less processing equipment and provides advantages of economy and through-put over wet granulation.
Wet Granulation--A wet granulation technique requires preparation of a blend, wetting the blend with a large amount of binder solution to a wet mass, milling the wet mass into moist granules agglomerated with a binder and drying the granules, followed by further milling and blending with other inactive ingredients. This is a lengthy and resource intensive process. For drugs that are not compressible and lack required flow characteristics, this process of agglomeration with a binder results in a compressible granulation.
Commercially available direct compression granulations of acetaminophen are prepared by a variety of wet granulation techniques utilizing a variety of inactive tableting ingredients and granulating equipment. A typical granulation is prepared in a conventional granulator, high sheer granulator or fluid bed granulator. Drying of the wet granular mass is usually achieved in a fluid bed dryer.
Aspirin is a commercial example of a direct compression tablet granulation prepared by the dry granulation technique. A typical granulation is prepared by blending aspirin with inactive tableting ingredients in a blender, compacting the blend using a roller compactor, milling to a desired particle size and reblending.
Tablet manufactures generally purchase direct compression granulations of large dosage drugs, such as aspirin or acetaminophen from suppliers who prepare such granulations by the methods described above. Crystalline aspirin is marginally compressible and hence suitable for compaction using slugging or roller compaction, thereby allowing the use of the dry granulation technique with only 10 percent added inactive tableting ingredients.
In contrast, crystalline acetaminophen is very hard and brittle and lacks any compressibility. Due to its poor compression characteristics, the drug cannot be tableted by the dry granulation technique described above.
The prior art has attempted to circumvent the costly wet granulation process by loading dry powder mixtures of acetaminophen with very high weight percents of inactive ingredients, e.g., 25 weight percent and higher, to achieve sufficient compressibility of the mixture for tablet manufacture, meaning only low dosage levels, e.g., 75 and lower weight percent of acetaminophen in a tablet produced by such methods.
Falzone et al, Drug Der Ind Phar 18(4): 468-489, examined the use of a roller compactor to prepare granulated material containing acetaminophen. The granulation contained 20% Avicel PH 101, 20% hydrous lactose and 60% of acetaminophen. The blends were roller compacted under various compactor parameters to assess their effect on particle size distribution and compressibility of the granulations obtained. The roller compaction resulted in a granulation with the same or smaller particle size than that of the starting material. The tablets obtained were very large 1/2" and 2" size compacts, prepared by using a research level motorized hydraulic press. The large amount of 40% of inactive ingredients in the blend mean only low dosage levels of acetaminophen are obtained in a tablet prepared by the procedure described by Falzone et al.
U.S. Pat. No. 3,639,169 discloses a compression vehicle component prepared for admixture with active materials with poor compression characteristics to provide a dry powder blend for direct compression into tablets. The compression vehicle itself is prepared by blending an inactive compressible material with other inactive tableting materials, roller compacting the blend into a sheet and then milling the sheet into granular particles to form the compression vehicle. As is evident from Example 13, in the pharmaceutical formulations set out at Column 10, lines 5 to 25, the compression vehicle constitutes the major proportion of the tablet formulation, e.g., 117 parts of the compression vehicle and only 25 parts of the drug.
Dry granulation would be a method of choice over wet granulation if a formulation and method could be discovered which could utilize the dry granulation technique to create direct compression tablet blends containing high dosage levels of acetaminophen. There is a substantial need in the art for a formulation and method to overcome the disadvantages inherent in the wet granulation method and produce a lower cost high quality granulation containing a high analgesic dosage level of acetaminophen capable of being directly compressed into a superior quality tablet.